2.1 Field of the Invention
The present invention relates to compositions and methods for preventing and treating metabolic disorders, especially disorders characterized by pathologic loss of appetite, adipose tissue, and lean body mass. More specifically, the present invention relates to compositions and methods for preventing and treating cachexia, especially cachexia associated with cancer and chronic renal insufficiency (CRI). The invention has relevance to the fields of biology, medicine, oncology, and pharmacology.
2.2 The Related Art
Catabolic wasting, or cachexia, is a syndrome characterized by: involuntary, progressive loss of both fat and skeletal muscle, refractoriness of weight loss to increased nutritional input, elevated resting energy expenditure (REE), decreased protein synthesis, altered carbohydrate metabolism (increased Cori cycle activity), hyper-catabolism of muscle via the ATP-ubiquitin-dependent proteasome pathway of proteolysis, and of adipose tissue via lipolysis (Body J J, Curr Opin Oncol 11:255-60, 1999, Muscaritoli M, et al: Eur J Cancer 42:31-41, 2006). Typically, at least 5% or 5 pounds of pre-illness body weight must have been lost before a patient is diagnosed with cachexia. Roughly half of all cancer patients experience some degree of catabolic wasting, with a higher occurrence seen in cases of malignancies of the lung, pancreas, and gastrointestinal tract (Dewys W D, et al: Am J Med 69:491-7, 1980). The syndrome is also found in patients having immunodeficiency disorders, such as AIDS, as well patients suffering bacterial and parasitic diseases, rheumatoid arthritis, and chronic diseases of the bowel, liver, kidneys, lungs, and heart. Cachexia is also associated with anorexia and can manifest as a condition in aging or as a result of physical trauma and burn injuries. The cachexia syndrome diminishes the patient's functional ability and quality of life, worsens the underlying condition and reduces tolerance to medications. The degree of cachexia is inversely correlated with the survival time of patients and it always implies a poor prognosis. In recent years, age-related diseases and disabilities have become of major health interest and importance.
Anorexia, a medical term for appetite loss, is a debilitating manifestation of many malignancies, and is observed in patients with cancer, infectious diseases, chronic organ failure, and trauma. Anorexia is a serious syndrome, because it leads to reduced caloric intake and malnutrition. Manifestations of anorexia include a decreased sense of taste and smell of food, early satiety, a decreased sense of hunger, and even outright aversion to food. Nausea and vomiting may be symptomatic as well. The etiology of anorexia is poorly understood; and effective treatment options are limited. Some studies suggest that a combination of hormonal, social, and psychological reasons may be important factors in the development and progression of the syndrome.
Despite the fact that cachexia is often associated with cancer, no consistent relationship has been demonstrated between the development of cachexia and tumor size, disease stage, and the type or duration of the malignancy. However, cancer cachexia is commonly associated with: reduced caloric intake, an increase in resting energy expenditure, and alterations in protein, fat, and carbohydrate metabolism. For example, some noted abnormalities in carbohydrate metabolism include: increased rates of total glucose turnover, increased hepatic gluconeogenesis, glucose intolerance and elevated glucose levels. Increased lipolysis, increased free fatty acid and glycerol turnover, hyperlipidemia, and reduced lipoprotein lipase activity are frequently noted as well. Importantly, the weight loss associated with cancer cachexia is caused not only by a reduction in body fat stores, but also by a reduction in total body protein mass and extensive skeletal muscle wasting. Increased protein turnover and poorly regulated amino acid oxidation may also be important factors in the progression of the syndrome. In addition, certain host-derived factors that are produced in response to the cancer, e.g., pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1, interleukin-6, and γ-interferon), acute phase proteins (such as C-reactive protein), and certain prostaglandins also seem to be associated with cancer cachexia.
In regards to cachexia associated with renal dysfunction, the basic pathophysiology is poorly understood. Chronic renal insufficiency (CRI) may result from any major cause of renal dysfunction. The most common cause of end-stage renal disease is diabetic nephropathy, followed by hypertensive nephroangiosclerosis and various primary and secondary glomerulopathies. There is a high prevalence of protein-energy malnutrition in both non-dialyzed patients with advanced chronic renal failure and in those individuals with end-stage renal disease who are receiving maintenance hemodialysis or chronic peritoneal dialysis therapy. The high prevalence of cachexia and malnutrition is of major concern because markers of protein-energy malnutrition are strong predictors of morbidity and mortality. Up to 40% of patients with chronic renal failure requiring hemodialysis or long-term peritoneal dialysis reportedly present weight loss and are associated with increased morbidity and mortality rates. Decreased levels of nitrogen stores and body weight and depleted visceral protein stores of albumin and transferrin are observed. Causes for malnutrition are multifactorial and include blood loss, protein and other nutrient loss during dialysis, catabolism due to chronic illness, and anorexia due to altered taste sensation, suboptimal oral intake, and depression (Kalantar-Zadeh K: Semin Dial 18:365-9, 2005).
Current methods for treating cachexia and anorexia have only limited benefit at best. As summarized by Yavusen (Yavuzsen T, et al: J Clin Oncol 23:8500-11, 2005), examples of randomized controlled clinical trials that yielded negative, mixed, or inconclusive results include trials with: Hydrazine sulfate, Cyproheptadine, Pentoxifylline, Melatonin, Erythropoietin with and without Indomethacin, Eicosapentaenoic Acid, Androgenic Steroids, Ghrelin, Interferon, and Dronabinol. Of all the drugs reviewed, only two types, corticosteroids and progestins, demonstrated consistently positive results in multiple randomized, controlled, clinical trials.
In particular the progesterone derivative, megestrol acetate, has been shown to increase appetite and weight (but not quality of life, survival, or functional ability) in cancer cachexia patients. Megestrol acetate and/or its metabolites may, either directly or indirectly, stimulate appetite, resulting in weight gain, or may alter metabolic pathways via interference with the production or action of mediators such as tumor necrosis factor-α. Evidence from clinical studies indicates that the increase in body weight observed during megestrol acetate therapy is related to the drug's appetite-stimulant or metabolic effects rather than its glucocorticoid-like effects or the production of edema.
The administration of β2-adrenergic-agonists (“β2-agonists”) is known to be associated with anabolic effects in humans (Choo J J, Horan M A, Little R A, et al, Am J Physiol 263:E50-6, 1992). The β2-agonists increase lean body mass by increasing protein synthesis and by interfering with the ATP-dependent ubiquitin-proteasome pathway (Lambert CP, Uc EY, Evans W J: Pharmacotherapy of Cachexia:311-324, 2005). Clinical trials have shown that β2-agonists can increase lean body mass in healthy athletes (Caruso J, Hamill J, Yamauchi M, et al: JAppl Physiol98:1705-11, 2005, Caruso J F, et al: Med Sci Sports Exerc 27:1471-6, 1995, Martineau L, et al: Clin Sci (Lond) 83:615-21, 1992), and in patients suffering from muscular dystrophy (Kissel J T, et al: Neurology 57:1434-40, 2001). β2-agonists administered by injection to rats and mice bearing highly cachectic tumors reportedly reduced or reversed muscle wasting (Busquets S et al., Cancer Res 64:6725 31 (2004); Carbo N et al., Cancer Lett 115:113 8 (1997); Costelli P et al., J Clin Invest 95:2367 72 (1995); Piffar P M et al., Cancer Lett 201:139-48 (2003)). Surprisingly, however, β2-agonists have not been studied in humans for prevention or treatment of cachexia in cancer or CRI. Furthermore, the β2-agonist, formoterol fumarate, specifically when administered via oral ingestion, has never been studied in either animals or in humans for prevention or treatment of cachexia in cancer, CRI. , or ageing sarcopenia. This latter observation is surprising insofar as formoterol fumarate is known to be orally bioavailable, and the oral route of administration affords significant benefits over other routes of administration (such as intraperitoneal injection, or inhalation) with respect to patient convenience and compliance. It is also surprising that formoterol fumarate has never been studied as a anti-cachectic preventive measure in either mammals or humans, because the anabolic effects of the drug should be effective in increasing the lean body mass and strength of individuals who are at risk of cachexia or who suffer from “pre-cachectic” metabolic imbalances but who have not yet suffered significant involuntary wasting.
Because cancer cachexia is associated with elevated levels of pro-inflammatory cytokines (TNF-α, IL6, CRP, and so forth), prior clinical studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (McMillan D C, et al: Br J Cancer 79:495-500, 1999), and indomethacin (Lundholm K, et al: Cancer Res 54:5602-6, 1994) can have beneficial effects. Macrolide antibiotics structurally-related to erythromycin are also known to possess anti-inflammatory properties (Amsden G W: J Antimicrob Chemother 55:10-21, 2005). Anti-inflammatory macrolides include clarithromycin, roxithromycin, and azithromycin. In small, non-randomized, and non-controlled clinical studies, Sakamoto and coworkers (Mikasa K, et al: Chemotherapy 43:288-96, 1997, Sakamoto M et al., Chemotherapy 47:444-51 2001) reported that treating non-small-cell lung cancer patients with clarithromycin increased the median survival time, reduced IL6 serum levels, and increased body weight. Randomized, controlled clinical trials with macrolides in cancer cachexia patients, however, have not been performed, and the effects of macrolides on performance status, quality of life, and functional performance in cancer cachexia patients have not been reported.
In the case of CRI, Kalantar-Zadeh (Kalantar-Zadeh K, Stenvinkel P, Bross R, et al: Kidney insufficiency and nutrient-based modulation of inflammation. Curr Opin Clin Nutr Metab Care 8:388-96, 2005 ) has shown that patients have a high cardiovascular mortality rate and that protein-energy malnutrition and inflammation have been implicated as the main cause of both cachexia and high mortality in these patients. These workers note that in this medical field, there is no consensus as to how to correct malnutrition and inflammation CRI patients, and that the complexity of the disease will probably require multiple intervention modalities. A review by Basaria S, (Basaria S, Wahlstrom J T, Dobs A S. Clinical review 138: Anabolic-androgenic steroid therapy in the treatment of chronic diseases.J Clin Endocrinol Metab. 2001 Nov;86(11):5108-17) proposes treatment with anabolic-androgenic steroids for severe weight loss associated with chronic renal disease.
Cachexia and anorexia thus, remain a frustrating and deadly problem for clinicians and patients. Both animal and human studies suggest that nutritional support alone is largely ineffective in replenishing lean body mass in the cancer-bearing host. Randomized trials exploring the usefulness of total parenteral nutrition support as an adjunct to cytotoxic antineoplastic therapy have, demonstrated little improvement in treatment results. See for example Brennan, M. F., and Burt, M. E., 1981, Cancer Treatment Reports 65 (Suppl. 5): 67 68. This, along with a clear demonstration that total parenteral nutrition can stimulate tumor growth in animals suggests the routine use of total parenteral nutrition in cancer treatment is not justified (Visner, D. L., 1981, Cancer Treatment Reports 65 (Suppl 5): 12).
The generally unsatisfactory results of cancer cachexia studies trials undertaken in the past 15 years, and the growing understanding that tumor- and/or host-driven metabolic imbalances on the molecular level may be important before significant weight loss is evident combine to suggest that cachexia/anorexia interventions should be taken in advanced cancer patients at the time of initial diagnosis, whether or not the patients initially present with significant weight loss. Muscaritoli et al (2006) address this point as follows: “several of the metabolic, biochemical and molecular alterations currently believed to be responsible for the phenotypic features of cachexia are already present upon first cancer diagnosis, even in the absence of significant body weight loss. Thus, the consolidated view is that cancer cachexia should be regarded to as an “early phenomenon”. The relevance of cancer cachexia in negatively affecting, not only patients' mortality, but also surgical risk, response to first- and second-line chemo-/radiotherapy, and not lastly quality of life, has progressively emerged during the recent years. Unfortunately, the predominant feature of cancer cachexia, i.e., the steadily progressive loss of muscle mass and function, has been shown to be only minimally reversible with the currently available nutritional, metabolic or pharmacological tools. Consequently, the development of early and effective interventions aimed at preventing rather than reversing the metabolic perturbations ultimately leading to muscle wasting and cachexia is now perceived as a mandatory need by the scientific community,”
Thus, there remains a need for better treatment options to help those suffering from cachexia and anorexia. There also remains a need to prevent the clinical manifestations of anorexia and cachexia from becoming significant in those individuals who are suffering from metabolic imbalances s associated with cachexia, but who have not yet experienced significant involuntary weight loss. The present invention addresses these and other needs.